Interference-free and high precision biosensor based on surface enhanced Raman spectroscopy integrated with surface molecularly imprinted polymer technology for tumor biomarker detection in human blood.

The reliable quantitative analysis of tumor biomarkers in circulating blood is crucial for cancer early screening, therapy monitoring and prognostic prediction. Herein, a novel biosensor combing surface-enhanced Raman spectroscopy (SERS) and surface molecularly imprinted polymer (SMIP) technology was developed for quantitative detection of carcinoembryonic antigen (CEA) that is closely related to several common cancers. Owing to the use of SMIP, recognition sites with high affinity to the target of interest can be well imprinted on the surface of SERS substrate, leading to a more stable and specific capture ability. In addition, two layers of core-shell nanoparticles were integrated to this SERS substrate to form highly efficient electromagnetic enhancement for SERS measurement via the generation of lots of “hot spot”. Besides, a unique Raman reporter (CC) with silent Raman signals at 2024 cm−1 was capsulated in the nanoparticles to avoid the optical noises originating from endogenous molecules at fingerprint region (300-1800 cm−1). Meanwhile, we employed an internal standard molecular (CN) to real time correct the fluctuating signals of Raman reporter when performing the quantitative analysis. Due to these features, a limit of detection (LOD) of 0.064 pg mL−1 with the detection range of 0.1 pg mL−1 - 10 μg mL−1 can be achieved by this assay. Excitingly, this technology even showed wonderful performances for CEA detection in real blood from cancer patients, demonstrating great potential for biomarker-based cancer screening.